1. Technical Field
The present invention relates to methods and pharmaceutical compositions involving the use of polymers for the closure of retinal breaks.
2. Background
Successful management of rheginatogenous retinal detachment is predicated upon closure of all retinal breaks. A rheginatogenous retinal detachment occurs when vitreous fluid passes through a hole in the retina and the retina separates from the retinal pigment epithelium. When retinal detachment is treated with vitrectomy, closure of retinal breaks generally requires creation of a chorioretinal adhesion around each break (Michels et al., Retinal Detachment, Klein E A, Ed. C V Mosby Co., St. Louis, Mo., 1990, pp 440, 847, 890-892). These adhesive lesions are generated with either laser photocoagulation or cryotherapy. Maximal chorioretinal adhesion is ordinarily achieved within 2 weeks following treatment (Bloch et al., Am J Opthalmol 71:666-673 (1971); Yoon et al., Ophthalmol 95:1385-1388 (1988)). To keep the retina in apposition with the retinal pigment epithelium during this time, prolonged intraocular tamponade with gas or silicone oil is utilized (Norton et al., Am J Ophthalmol 68:1011-1021 (1969); Norton et al., Trans Am Acad Ophthalmol Otolaryngol 77:85-98 (1973); Lean et al., Trans Ophthalmol Soc (UK) 102:203-205 (1982); Gonvers M, Ophthalmologica 184:210-218 (1982); Petersen J., Graefe""s Arch Clin Exp Ophthalmol 225:452-456 (1987)).
When long acting gases such as SF6 or C3F8 are used, patients often must keep their head in a face down position for 2 weeks after surgery (Michels et al., Retinal Detachment, Klein E A, Ed. C V Mosby Co., St. Louis, Mo., 1990, pp 890-892). This causes considerable discomfort in most patients, and not uncommonly, is the most difficult hurdle in post-operative management. Additionally, intraocular gas may be associated with a number of ocular complications including, cataract, glaucoma, corneal edema, and creation of retinal folds (Fineberg et al., Am J Ophthalmol 79:67-76 (1975); Abrams et al., Am J Ophthalmol 94:165-171 (1982); Foulks et al., Arch Ophthalmol 105:256-259 (1987); Lewen et al., Arch Ophthalmol 105:1212-1214 (1987)). Another potential disadvantage of gas as an intraocular tamponade is that by sequestering inflammatory factors between the bubble interface and the retina, it may promote scar tissue formation on the retinal surface (Charles, S., Vitreous Microsurgery, Williams and Wilkins, Baltimore, Md., 1987, p 135). As this scar tissue contracts, it can distort the retinal surface, and may cause re-detachment of the retina (proliferative vitreoretinopathy) (Machemer R., Brit J Ophthalmol 62:737-747 (1978); Laqua et al., Am J Ophthalmol 80:913-929 (1975)).
Using silicone oil as a post-operative intraocular tamponade has the advantage that the patient is not required to position face down for more than one day post-operatively. However, unlike gas, which is slowly reabsorbed into the blood stream, silicone must be surgically removed from the eye as a secondary procedure to prevent silicone induced ocular complications such as cataract, glaucoma, band keratopathy, corneal decompensation and promotion of proliferative vitreoretinopathy (PVR) (Federman et al., Ophthalmol 95:870-876 (1988); Sternberg et al., Arch Ophthalmol 102:90-94 (1985)).
Other less effective methods of retinal fixation to the underlying retinal pigment epithelium include retinal tacks (de Juan et al., Am J Ophthalmol 99:272-274 (1985); Burke et al., Arch Ophthalmol 105:404-408 (1987)), and cyanoacrylate glue (McCuen et al., Am J Ophthalmol 102:199-207 (1986)). Titanium or stainless steel metal retinal tacks have been used to attach the retina to the eye wall to treat giant retinal tears or after large relaxing retinotomies. The tacks do not create a confluent chorioretinal adhesion around the retinal tear and thus require supplemental laser or cryotherapy as well as intraocular tamponade with gas or silicone oil. Tacks are also associated with complications such as choroidal hemorrhage and dislodgment (Lewis et al., Am J Ophthalmol 103:672-680 (1987)).
Butyl-2-cyanocrylate glue has been used to close retinal breaks in animal models of experimental retinal detachment (McCuen et al; Hida et al., Am J Ophthalmol 103:782-789 (1987); Hida et al., 1988). The glue is applied directly to retinal holes, polymerizing rapidly to form a seal over the retinal hole. While successful at closing the break and creating a chorioretinal adhesion, some intraocular glues can cause local retinal toxicity, possibly from release of formaldehyde and cyanoacetate (Hida et al., 1987).
Patients suffering from retinal detachment are in need of a better method for temporarily closing retinal breaks while chorioretinal adhesions form, thus allowing recovery from surgery with a minimum of discomfort and/or ocular complications.
The present invention is directed to compositions, methods, and articles of manufacture for the closure of retinal breaks by applying a polymer formulation to the retinal surface in the vicinity of the retinal break. The invention provides methods for closing a retinal break in a mammal, comprising applying to the retinal surface over and around the retinal break a non-toxic polymer formulation comprising at least one polymer precursor, and transforming the polymer formulation into a gel-like coat. In a preferred embodiment, the polymer formulation comprises a photochemically reactive polymer precursor species that can be transformed from a liquid to gel form by exposure to light. Another preferred composition includes a mixture of two mutually reactive polymer precursors.
The invention also provides methods for the management of retinal detachment, comprising replacing the vitreous with gas, creating a chorioretinal adhesion around a retinal break, applying to the retinal surface over and around the retinal break a non-toxic polymer formulation comprising at least one polymer precursor, and transforming the polymer into a gel-like coat.
Also provided are methods for preventing proliferative vitreoretinopathy, comprising applying a non-toxic polymer formulation over and around the retinal break and extending beyond the break by a substantial amount, preferably to cover more than 75% of the retina.
In addition, the invention provides pharmaceutical compositions, methods for preparing such pharmaceutical compositions, and articles for manufacture for use in the methods described above.
This invention pertains to the field of retinal surgery, particularly to the closure of retinal breaks. The invention provides a superior alternative to silicone oil or intraocular gas for post-operative tamponade. The methods of the invention comprise the application of a polymer formulation to the retinal surface over and around the retinal break. More extensive applications of the polymer formulation to the retinal surface can prevent post operative scar tissue formation and recurrent retinal detachment (proliferative vitreoretinopathy). The polymer formulation is applied in liquid form, assuring conformity to irregular tissue surfaces. It is then transformed to a thin, gel-like coat by photopolymerization with a light source. Alternatively, a liquid polymer precursor that auto-polymerizes is applied over the break and adjacent retina. The polymerized gel is bound to the retina and retinal pigment epithelium, and resists displacement with overlying turbulent fluid flow. It is water permeable and allows diffusion of small molecules such as oxygen, glucose and other essential nutrients. While the polymer adheres to the retina, it closes the retinal hole, preventing fluid from passing into the subretinal space.
Before or after application of the polymer formulation to the retinal surface, laser photocoagulation or cryotherapy can be applied around the break to form a chorioretinal adhesion, which reaches adequate strength to prevent retinal detachment by about 10-14 days after surgery (Yoon et al.). Typically laser is applied around an extra-macular hole, but not around macular holes. During this time, the polymer slowly biodegrades, but remains in place long enough to maintain retinal attachment and allow the retinopexy adhesion to reach maturity. Because the polymer closes the hole, the vitreous cavity can be filled with balanced saline solution at the end of surgery and no additional intraocular tamponade is required with gas or silicone. Therefore, patients avoid the difficulty of post-operative positioning if gas is used and avoid a second procedure to remove silicone oil if it is used instead of gas. Furthermore, complications associated with gas or silicone oil are avoided.
In addition to obviating the need for gas or silicone tamponade, wider application of the polymer formulation beyond the retinal break, to a portion of or the entire retinal surface, has the added benefit of preventing post-operative scar tissue formation on the retinal surface, which can distort the retinal surface and reopen retinal breaks (proliferative vitreoretinopathy, PVR). This is due in part to the fact that larger molecules, including proteins and cells which cause proliferative vitreoretinopathy, cannot traverse or adhere to the polymer formulation, and thus will not bind to the underlying retina during the post-operative period (West et al., Proc Natl Acad Sci (USA) 93:13188-13193 (1986)).
One aspect of the invention is a method for closing a retinal break in an animal, comprising applying a non-toxic polymer formulation to the retinal surface of the animal over and around the retinal break, and transforming the polymer formulation into a gel-like coat. Preferably, the resultant gel-like coat comprises a biodegradable polymer. By xe2x80x9cretinal breakxe2x80x9d is meant a hole, tear, or other abnormal opening in the retina (also known as the neurosensory retina). Retinal breaks can develop from several conditions, including, but not limited to, myopia, congenital defects, trauma, and cataract surgery. Preferably the animal is a laboratory animal or domesticated animal, is more preferably a mammal, and most preferably is a human. Suitable laboratory animals include mice, rats, rabbits, monkeys, apes and other research animals. Suitable domesticated animals include dogs, cats, cattle, horses, goats, sheep, pigs, mules, donkeys, and other animals in the service or company of man.
A key feature of the requirements for the materials to be used in closing retinal breaks is that they adhere to the retina over and around the break. One way to provide for this feature is to produce the material implant from a liquid polymer precursor applied directly on and around the site of the retinal defect. By xe2x80x9cpolymerxe2x80x9d is meant a molecule formed by the union of two or more monomers. A xe2x80x9cmonomerxe2x80x9d is a repeating structure unit within a polymer. xe2x80x9cPolymerizationxe2x80x9d is the bonding of two or more monomers to produce a polymer. For example, polymerization of ethylene forms a polyethylene chain, or polymerization of a monomer X and a monomer Y can yield a polymer with the repeating subunit X-Y. It will be appreciated that polymers can also be formed by the polymerization of more than two monomers and that two or more monomers can be present in unequal ratios in the resultant polymer. By xe2x80x9cpolymer precursorxe2x80x9d is meant a molecule that is subsequently linked by polymerization to form a polymer, which is larger than the polymer precursor. As discussed in greater detail below, polymerization can be achieved in various ways, such as by photopolymerization, autopolymerization, or physicochemical polymerization. The polymer precursor can itself be a polymer, such as, for example, poly(ethylene glycol). Alternatively, the polymer precursor can be a molecule other than a polymer, such as a protein, for example, albumin, collagen, gelatin, or other non-polymeric molecules.
The polymer precursor is usually present in the polymer formulation at a concentration in a range of about 0.01% to about 90%. The actual concentration varies with the polymer precursor used and its toxicology. Most polymer precursors are preferably used at a minimal concentration of about 5% because at lower concentrations it may be difficult to form a gel. However, by increasing the hydrophobicity of the ends of the polymer precursor, concentrations as low as about 1%, preferably about 3%, can be used to form a gel. High molecular weight precursors (i.e., greater than about 70,000 g/mol, preferably greater than about 100,000 g/mol), such as, for example, acrylated hyaluronic acid are preferably present at a concentration not greater than about 1%. See, for example, U.S. Pat. Nos. 5,801,033; 5,820,882; 5,626,863; and 5,614,587, incorporated herein by reference.
Transformation of the polymer precursor to a thin, gel-like coat can be accomplished in a number of ways, for example, by photochemical reactivity, by chemical reactivity, and by physicochemical response. When such a liquid-to-solid transition occurs directly upon the tissue surface, via any of the approaches described above, the resulting biomaterial implant adheres to the tissue surface. Liquid polymer precursor is applied over and around the retinal break, covering the breached area of the retina and overlapping the unbreached area of the retina by an amount sufficient to maintain adhesion of the polymerized implant to the retinal surface. Typically, the polymerized implant extends over the unbreached area of the retina by about 0.1 mm to about 5 mm, and can extend over a substantial portion of the retinal surface if desired, up to the entire retinal surface. Preferably the polymerized implant extends over the unbreached area of the retina by about 0.5 mm to about 2 mm.
The transformation of polymer precursor into a gel-like coat can be achieved by photopolymerization of the polymer formulation. Photochemically activatable polymer precursors suitable for the methods of the invention include precursors comprising a water-soluble polymer as the central domain, such as, for example, poly(ethylene glycol) (PEG)-based polymers. PEG is a polymer of the formula HOCH2(CH2OCH2)nCH2OH, wherein n is an integer giving rise to molecules ranging in molecular weight typically from about 200 g/mol to greater than about 75,000 g/mol, preferably between about 6,000 g/mol to about 35,000 g/mol. Some specific PEG molecules have a molecular weight of about 400, 1350, 3350, 4000, 6000, 8000, 18500, 20000, or 35000. PEG molecules having a molecular weight not specifically listed, but nonetheless within a range of about 200 g/mol to greater than about 75,000 g/mol are also contemplated. Lower molecular weight PEG formulations are referred to as short chain PEG formulations and typically have a molecular weight of about 4,000 g/mole or less. Higher molecular weight PEG formulations are referred to as long chain PEG formulations and have a molecular weight of greater than about 4,000 g/mol, preferably greater than about 8,000 g/mol, and can be greater than about 10,000 g/mol,,and greater than about 20,000 g/mol. Preferably the long chain PEG formulations have a molecular weight in the range of about 7,000 g/mol to about 20,000 g/mol, with about 8,000 g/mol to about 10,000 g/mol being most preferred. One of ordinary skill in the art expects PEG molecules to be present in a distribution centered around the stated molecular weight, commonly as much as plus or minus about 20% of the stated molecular weight. Vendors often list the molecular weight of a PEG product as an average molecular weight (See, for example, the Sigma catalog).
Preferably the polymer precursors of the invention comprise reactive termini to allow for photopolymerization, such as, for example, free radical polymerizable termini. Examples of such reactive termini include acrylates and methacrylates, with acrylates being more preferred. Preferably the polymer precursor is a PEG diacrylate or tetracrylate.
Preferably the polymer precursor also comprises degradable regions of a molecular weight, relative to that of the water-soluble central domain, to be sufficiently small that the properties of the polymer precursor in solution, and the gel properties, are determined primarily by the central water-soluble chain. Typically the polymer precursor comprises about 0% to about 20%, preferably about 1% to about 10%, degradable regions. Examples of such degradable regions include, but are not limited to, hydrolytically labile oligomeric extensions, such as, for example, poly(xcex1-hydroxy esters). Examples of poly(xcex1-hydroxy esters) include poly(dl-lactic acid) (PLA), poly(glycolic acid) (PGA), poly (3-hydroxybutyric acid) (HBA), and polymers of xcex5-caprolactone. The hydrolytic susceptibility of some of the ester linkages is in the following order: glycolidyl greater than lactoyl greater than xcex5-caprolactyl.
In a preferred embodiment, the polymer precursor has the formula:
Pmxe2x88x92Dnxe2x88x92Woxe2x88x92Dpxe2x88x92Pq
wherein W is a water-soluble polymer; D is a degradable moiety; P is a photopolymerizable moiety; m and q are integers from 1 to about 10; o is an integer from I to about 100; and n and p are integers from 0 to about 120. W can be a linear polymer or a branched polymer. One of ordinary skill in the art would understand the formula provided above to include branched polymers having more than two termini and having degradable and/or photopolymerizable moieties on some or all of the termini of the branched polymer. A xe2x80x9cdegradable moietyxe2x80x9d is an oligomeric compound that when integrated into a polymer precursor, creates within the polymer precursor a degradable region as described above. A xe2x80x9cphotopolymerizable moietyxe2x80x9d is a moiety that allows the polymer precursor to polymerize upon exposure to light. Some wavelengths suitable for catalyzing polymerization are discussed in more detail below.
Typically, the values of m and q are varied so as to achieve the desired degree of cross-linking and rate of transition from liquid-to-gel upon polymerization. The values of n and p are varied so as to achieve a desirable percentage of the degradable moiety, preferably between about 0.1% to about 25% degradable moiety, with about 1% to about 10% being most preferred. One of ordinary skill in the art would know to vary the values for n and p according to the value of o and the molecular weight of W in order to achieve this goal. Preferably m and q are integers from 1 to about 5, n and p are integers from 0 to about 10, and o is an integer from 1 to about 40. Alternatively, the polymer formulation can comprise in varying molar ratios polymer precursors having differing values for m, n, o, p and q so as to achieve a desirable percentage of the degradable moiety upon polymerization. For example, if W is a water soluble polymer having a molecular weight of at least 4,000 g/mol and o=1, n and p are integers from 0 to about 60, more preferably from 0 to about 25, even more preferably 1 to about 15, with 1 to about 5 being most preferred. Preferably W is a PEG molecule having a molecular weight from about 200 g/mol to about 75,000 g/mol. Preferably, if W is a PEG molecule having a molecular weight greater than 4,000, o is an integer from 1 to about 5, with 1 being most preferred.
Preferably the polymer precursor comprises a PEG central chain with degradable regions and photopolymerizable end groups that terminate the degradable regions. The polymer precursors of the invention can be synthesized by methods known in the art (Sawhney et al., Macromolecules (1993) 26:581-587; Hill-West et al., Proc. Natl. Acad. Sci. USA (1994) 91:5967-5971) and described herein in Examples 1-3.
A preferred polymer chain comprises lactic acid, glycolic acid or epsilon-caproic acid in the degradable region D. Incorporation of oligolactic acid into the polymer will increase its hydrophobic content. The polymer""s hydrophobic content, and hence its strength of adhesion, varies directly with its % oligolactic, oligoglycolic, or oligoepsilon-caproic acid content. PEG is used to initiate the ring-opening polymerization of dl lactide, ll lactide, glycolide, or epsilon caprolactone to an extent such that from about 0.1% to about 25%, preferably about 1% or 10%, of the mass of the polymer chain is comprised of oligolactic acid, oligoglycolic acid, or oligoepsilon-caproic acid. This ratio is controlled via the reaction stoichiometry: the polymerization, if performed on dry polymer precursor, will produce very little lactic acid, glycolic acid, or epsilon-caproic acid homopolymer.
Biocompatibility of various biodegradable polymers can easily be assessed as described in Example 6 by injecting rabbits intravitreally with a polymer formulation, photopolymerizing the polymer precursor, and observing the animal clinically or histologically for signs of intraocular inflammation or toxicity.
The polymer precursors can be photopolymerized to form cross-linked networks directly upon the retinal surface. In addition to the polymer precursors, the biodegradable polymer formulation can also comprise reagents to facilitate the photopolymerization process, such as at least one photoinitiator, and one or more co-catalysts, such as, for example, N-vinylpyrrolidone and triethanolamine. Preferably a nontoxic photoinitiator such as eosin Y photoinitiator is used. Other initiators include 2,2-imethoxy-2-phenylacetophenone and ethyl eosin. The polymerization process can be catalyzed by light in a variety of ways, including UV polymerization with a low intensity lamp emitting at about 365 nM, visible laser polymerization with an argon ion laser emitting at about 514 nM, visible illumination from a conventional endoilluminator used in vitreous surgery, and most preferably by illuminating with a lamp that emits light at a wavelength between 400-600 nM, such as, for example, a 1-kW Xe arc lamp. Illumination occurs over about 1-120 seconds, preferably less than 30 seconds. Since the heat generated is low, photopolymerization can be carried out in direct contact with cells and tissues. Indeed, similar materials have been successfully utilized for the encapsulation of pancreatic islet cells and for the prevention of post-operative adhesion formation (Hill-West et al. Obstet Gynecol 83: 59-64 (1994).
Alternatively, the transformation of the polymer formulation into a gel-like coat can be achieved by autopolymerization of the polymer formulation. Auto-chemically reactive polymer gels may be formed by mixing two or more mutually reactive polymer precursors to result in a cross-linked polymer network. Usually, the polymer formulation comprises a first polymer precursor and a second polymer precursor, the first and second polymer precursors being mutually reactive. Preferably the first and second polymer precursors are present in about equimolar amounts. Typically, at least one of the reactive polymer precursors is a PEG based polymer precursor. Preferably, both polymer precursors are PEG based polymer precursors.
Suitable first polymer precursors include proteins, such as, for example, albumin, proteins derived from skin, connective tissue, or bone, such as collagen or gelatin, other fibrous proteins and other large proteins, tetra-amino PEG, copolymers of poly(N-vinyl pyrrolidone) containing an amino-containing co-monomer, aminated hyaluronic acid, other polysaccharides, and other amines. Preferably the tetra-amino PEG has a molecular weight of at least about 3,000 g/mol, preferably more than about 6,000 g/mole, even more preferably more than about 10,000 g/mol, and more preferably at least about 20,000 g/mol.
Suitable second polymer precursors include, but are not limited to, terminally-functionalized PEG, such as difunctionally activated forms of PEG. Some activating groups include epoxy groups, aldehydes, isocyanates, isothiocyanates, succinates, carbonates, propionates, etc. Examples of such forms of PEG include, but are not limited to, PEG di-succinimidyl glutarate (SG-PEG), PEG di-succinimidyl (S-PEG), PEG di-succinimidyl succinamide (SSA-PEG), PEG di-succinimidyl carbonate (SC-PEG), PEG di-propionaldehyde (A-PEG), PEG succinimidyl propionate, and PEG di-glycidyl ether (E-PEG) (U.S. Pat. No. 5,614,587) and other epoxy-derivatized PEG molecules, PEG nitrophenyl carbonate, PEG dialdehydes, PEG di-isocyanates, PEG di-isothiocyanates, and the like. Particularly preferred is a di-N-hydroxysuccinimidyl-activated dicarboxyl (PEG), such as a di-N-hydroxysuccinimidyl PEG. Other suitable difunctionally activated forms of PEG can be obtained from the Shearwater Polymers Catalog (see, for example, the xe2x80x9cElectrophilically Activatedxe2x80x9d section of their website at http://www.swpolymers.com).
Preferred autochemically reactive polymer precursor pairs include (1) a tetra-amino PEG and a di-N-hydroxysuccinimidyl PEG; (2) a tetra-amino PEG and a di-succinimidyl carbonate PEG; (3) collagen, gelatin, or albumin and a di-N-hydroxysuccinimidyl PEG; (4) collagen, gelatin, or albumin and a di-succinimidyl carbonate PEG; and (5) other suitable autochemically reactive polymer pairs. Most preferred for the methods of the invention is the combination of a tetra-amino PEG and a di-N-hydroxysuccinimidyl PEG. If a di-N-hydroxysuccinimidyl active PEG is mixed with a di-amino PEG, a high molecular weight polymer results, but not a cross-linked hydrogel. However, if a di-N-hydroxysuccinimidyl activated PEG is mixed with a tetra-amino PEG, a cross-linked hydrogel network is formed, liberating only N-hydroxysuccinate as a reaction product. N-hydroxysuccinate is water-soluble and of very low toxicity. Preferably the di-N-hydroxysuccinimidyl PEG used in combination with a tetra-amino PEG is a di-N-hydroxy-succinimidyl activated succinate-terminated PEG. Di-N-hydroxy-succinimidyl activated glutarate-terminated PEG is less preferred because, when used in combination with a tetra-amino PEG, can produce ocular inflammation. These hydrogels can degrade by spontaneous hydrolysis at the linking group at the end of the polymer chain and can degrade within the protein backbone of a protein-containing gel. With gels formed from a PEG-containing first component and a PEG-containing second component, one can include a hydrolytically degradable oligolactic acid, oligoglycolic acid, or oligoepsilon-caproic acid domain, for example. Gels formed from protein-based, peptide-based, or polysaccharide-based precursors can also degrade under the enzymatic influences of the body.
Biocompatibility of various reactive polymer precursor pairs can easily be assessed as described in Example 7 by injecting a rabbit intravitreally with a mixture of the members of the polymer precursor pair, and observing the animal visually or histologically for signs of intraocular inflammation or toxicity.
The extent of incorporation into the gel phase can be optimized by manipulating various parameters, such as the pH of the reaction solution and the ratio of the first polymer precursor to the second polymer precursor. Typically, when PEG tetra-amine and di-N-hydroxy succinimidyl PEG are to be used, polymer precursors are separately reconstituted immediately before use in physiological saline at pH 8. They are mixed to yield a total final concentration of about 10% using an optimal ratio of molar amounts of each precursor, preferably equimolar. Given that reaction begins immediately after mixing, injection onto the retina is preferably performed immediately. The mixing is performed with two syringes and a connector. Alternatively, a syringe with two barrels can be used. Static mixture occurs on the tip of the syringe immediately before the polymer precursor solutions pass through a needle or cannula. The time between the initiation of mixing and injection is usually less than about 30 seconds. This can be achieved by positioning a 30 gauge cannula (or other suitable sized cannula, or a needle) attached to a syringe(s) containing polymer over the break prior to mixing the components.
Toward physicochemical transition, block copolymers of poly(ethylene glycol)xe2x80x94poly(propylene glycol)-poly(ethylene glycol), commonly referred to as Pluronics(trademark), can be used to form polymer solutions that are liquid at 4xc2x0 C. but gels at 37xc2x0 C., permitting injection of the cold fluid with solidification to form a physicochemically cross-linked polymer network on the surface of the tissue. Other thermoreversible biocompatible biodegradable polymers are known. For example, Jeong et al., Nature (1997) 388:860-862, recently described copolymers of PEG and lactic acid that display favorable liquid-to-solid gelation transitions. Such materials can either be applied warm and fluid and allowed to cool in vivo into a gel form, or can be applied cool and fluid and allowed to warm in vivo into a gel form, depending upon the physicochemical characteristics of the gel and its precursor.
Polymers that display a physicochemical response to stimuli have been explored as potential drug-delivery systems. Stimuli studied to date include chemical substances and changes in temperature, pH and electric field. Homopolymers or copolymers of N-isopropylacrylamide and poly(eythlene oxide)-poly(propylene oxide)-poly(ethylene oxide) (known as poloxomers) are typical examples of thermosensitive polymers, but their use in drug delivery is problematic because they are toxic and non-biodegradable. Biodegradable polymers used for drug delivery to date have mostly been in the form of injectable microspheres or implant systems, which require complicated fabrication processes using organic solvents. Such systems have the disadvantage that the use of organic solvents can cause denaturation when protein drugs are to be encapsulated. Furthermore, the solid form requires surgical insertion, which often results in tissue irritation and damage. The methods of the invention involve the synthesis of a thermosensitive, biodegradable hydrogel consisting of polymer precursor blocks of poly(ethylene oxide) and poly(L-lactic acid). Aqueous solutions of these polymer precursors exhibit temperature-dependent reversible gel-sol transitions. By xe2x80x9csolxe2x80x9d is meant a polymer precursor solution which is more liquid than solid. By xe2x80x9cgelxe2x80x9d is meant a polymer solution which is more solid than liquid. The hydrogel can be loaded in an aqueous phase at an elevated temperature (around 45 degrees C), where they form a sol. In this form, the polymer is injectable. On subcutaneous injection and subsequent rapid cooling to body temperature, the loaded copolymer forms a gel.
The polymer formulations described above are applied in a manner consistent with the surgical procedure as a whole. Typically, the subretinal fluid is drained with fluid/gas exchange in order to flatten the retina. Laser photocoagulation or cryotherapy can then be performed around the break. The polymer formulation is then applied to the retinal surface as described above. Polymerization is effected as discussed above. Usually at least about 1 second to five minutes or longer is allowed to pass to ensure complete polymerization has occurred, and preferably the delay is less than 30 seconds. The gas is then removed and replaced with a balanced saline solution.
Another aspect of the invention is a method for management of retinal detachment in an animal, comprising applying a non-toxic, biodegradable polymer formulation to the retinal surface of the animal over and around the retinal break, and transforming the polymer formulation into a gel-like coat. As discussed above, closure of the retinal break prevents fluid iS from leaking into the potential space between the retina and the retina pigment epithelium. If desired, chorioretinal adhesions can be created, preferably by laser photocoagulation before or after application of the biodegradable polymer. A xe2x80x9cchorioretinal adhesionxe2x80x9d is an adhesion between the retina and underlying retinal pigment epithelium and choroid.
Yet another aspect of the invention is a method for the prevention of proliferative vitreoretinopathy (PVR), comprising applying a non-toxic, biodegradable polymer formulation more extensively to the retinal surface of an animal in need thereof than otherwise applied to close a retinal break. Preferably the polymer formulation is applied to at least about 25% of the retinal surface surrounding the retinal break, preferably to more than about 50% and applications to more than about 75% of the retinal surface to the entire retinal surface are most preferred. In a preferred embodiment, autopolymerizable polymer precursors are applied to the retinal surface as described above. In another preferred embodiment, a polymer precursor solution containing at least one photoinitiator is applied to the retinal surface around the retinal hole. Polymerization is then effected by any of the methods described above to close the retinal break. The eye is then filled with a solution containing at least one photoinitiator but no polymer precursor to coat the surface of the retina. Excess photoinitiator is drained from the eye. Next, polymer precursor solution that does not contain photoinitiator is applied to the remainder of the retinal surface and polymerization is again effected. The polymerization reaction results in a thin, transparent gel where the polymer precursor contacts the photoinitiator, but not in areas free of photoinitiator. This results the formation of a gel only on the surface of the retina. The eye is once again filled with fluid. Unpolymerized precursors are then irrigated from the eye. The adherent polymer biodegrades over a 2-10 week period. The polymerized gel overlying the retina both closes the retinal break and prevents adherence of scar tissue that could cause proliferative vitreoretinopathy and recurrent retinal detachment. Another embodiment omits the initial step of applying a polymer precursor solution containing photoinitiator directly to the hole.
A further aspect of the invention is the use of at least one non-toxic, biodegradable polymer precursor for the preparation of a pharmaceutical composition for closing a retinal break in a mammal. Suitable polymer precursors and other components of the pharmaceutical composition are discussed in detail above in the sections describing the components of suitable polymer formulations. Additional components can include any other reagents that catalyze polymerization of the polymer precursor, pharmaceutically suitable delivery vehicles for ocular administration, such as for delivery to the interior of the eye, and any other pharmaceutically acceptable additives.
The invention also provides articles of manufacture for use in closing a retinal break in a mammal with a non-toxic biodegradable polymer. In one embodiment, the article of manufacture comprises a first container comprising a polymer precursor of the formula:
Pmxe2x88x92Dnxe2x88x92Woxe2x88x92Dpxe2x88x92Pq
wherein W is a water-soluble polymer; D is a degradable moiety; P is a photopolymerizable moiety; m and q are integers from 1 to about 10; o is an integer from 1 to about 100; and n and p are integers from 0 to about 120. The first container can optionally contain at least one photoinitiator and can also optionally contain at least one co-catalyst. Where the first container does contain a photoinitiator in addition to the polymer precursor, the article of manufacture can optionally contain a second container comprising polymer precursor but no photoinitiator. The article of manufacture can optionally contain a third container comprising a photoinitiator solution but no polymer precursor. An article of manufacture comprising all three containers or just the second and third containers are useful for preventing PVR as described above. An article of manufacture comprising the first container only is sufficient for closing retinal breaks. The article of manufacture preferably further comprises instructions for use according to the methods described above involving photopolymerization.
In another embodiment, the article of manufacture comprises a first container comprising a first polymer precursor and a second container comprising a second polymer precursor, the first and second polymer precursors being mutually reactive. The first and second polymer precursors can be present in the container in admixture with a pharmaceutically suitable vehicle for delivery to the interior of the eye. Alternatively, any such vehicle can be added separately, if necessary, for example, to reconstitute the polymers. Suitable first and second polymer precursors are any of those polymer precursor pairs discussed above that can autopolymerize. Preferably the first polymer precursor is albumin, collagen or gelatin, and the second polymer precursor is a terminally-functionalized poly(ethylene glycol) (PEG). Typically, the first and second containers are separate syringes or are separate barrels of a single syringe having static mixture device at the tip of the syringe, and can also be vials or other cylindrical containers, such as, for example a segment of tubing. The article of manufacture can further comprise printed instructions for a method for closing a retinal break by combining the first and second polymer precursors immediately before applying to the retinal surface of the mammal over and around the retinal break. Usually, the first and second polymer precursors are combined by extruding from each container simultaneously into and through a connector onto the retinal surface. Suitable connectors are any structures that permit mixing of the first and second polymer precursors immediately before application to the retinal surface, such as, for example, a structure that is Y-shaped and comprises two tubular segments, each of which fits over an aperture in each container, and which are united into a single tubular segment.
The following examples illustrate, but in no way are intended to limit the present invention.